Estrogens are an important class of steroidal hormones that stimulates the development and maintenance of fundamental sexual characteristics in humans. In addition, estrogens have been demonstrated to affect a variety of diverse biological processes. Many of the incidental effects of estrogens are positive, including the maintenance of bone density, central nervous system function and preservation of memory. However, estrogens also have been demonstrated to have serious negative effects, including promoting the development of breast and endometrial cancers.
Based upon a life expectancy of nearly eighty years in the United States, a woman can expect to spend about a third of her lifetime in a post-menopausal state. A woman's estrogen levels drop dramatically during menopause and menopausal women often experience many side affects associated with the reduction in estrogen production. To treat these conditions, physicians often prescribe hormone replacement therapy, which primarily consists of the administration of estrogen in combination with progestin.
In light of the more serious side effects associated with current hormone replacement therapy, including increased risk of ischemic stroke, myocardial infarction, thromboembolism, cerebrovascular disease, and endometrial carcinoma, a significant amount of research has been carried out to identify effective nonsteroidal estrogen and antiestrogenic compounds.
A large number of compounds have been described that either mimic or block the effects of the most potent estrogen, 17β-estradiol. Compounds that bind to an estrogen receptor and stimulate many of the same biological effects as 17β-estradiol are termed “estrogen receptor agonists.” Compounds that inhibit the binding of 17β-estradiol to an estrogen receptor or interfere with the effects of 17β-estradiol binding to an estrogen receptor are referred to as “estrogen receptor antagonists.” Compounds that affect different estrogen receptors with different potencies are typically referred to as selective estrogen receptor modulators (SERMs). SERMs may act as either agonists or antagonists to selectively modulate one or more estrogen receptors. Certain SERM compounds have mixed estrogenic and anti-estrogenic activities and act as estrogen receptor agonists in some tissues and as estrogen receptor antagonists in other tissues.
Estrogens, such as 17β-estradiol, have been thought to exert their effects by binding to one of two nuclear estrogen receptors, (ER)α or (ER)β. Because (ER)α and (ER)β are found in different tissues and have been demonstrated to have different biological roles, researchers have focused on the development of SERMs that effect a response by selectively binding to either (ER)α or (ER)β.
Two examples of nonsteroidal SERMs that exhibit different activities towards (ER)α and (ER)β are tamoxifen and raloxifene. Tamoxifen and raloxifene have been developed for the treatment and/or prevention of osteoporosis, cardiovascular disease and breast cancer in addition to the treatment and/or prevention of a variety of other disease states. Both compounds have been shown to exhibit an osteoprotective effect on bone mineral density combined with a positive effect on plasma cholesterol levels and a greatly reduced incidence of certain types of cancer. Unfortunately, tamoxifen and raloxifene both induce side effects such as hot flushes and tamoxifen promotes life-threatening disorders, such as endometrial cancer.
The present disclosure includes novel nonsteroidal SERMs that elicit the desired effects of hormone replacement therapy without inducing the negative effects of hormone replacement therapy or those of known selective estrogen receptor modulators.